Biodegradable oxidized cellulose esters

ABSTRACT

The present invention relates to the preparation of a series of oxidized cellulose esters suitable for use as a drug carrier in the development of biodegradable controlled and/or sustained release pharmaceutical, agricultural, and veterinary compositions, such as films, compacts, microspheres, and pellets. The esters are prepared by acylation of oxidized cellulose having at least 3% carboxyl groups. The resulting oxidized cellulose esters are soluble in aqueous alkaline solutions, water, and a variety of organic solvents.

FIELD OF THE INVENTION

[0001] This invention is related to the preparation of oxidizedcellulose esters suitable for use in the development of pharmaceuticalcompositions.

BACKGROUND OF THE INVENTION

[0002] Oxidized celluloses containing 3-25.6% (w/w) carboxylic contentrepresent an important class of biodegradable polymers. Ashton, U.S.Pat. No. 3,364,200 (1968). They are prepared from cellulose, the mostabundant natural polymer, by treatment with an oxidant under controlledconditions. See e.g. Heinze and Glasser (1998).

[0003] Oxidized cellulose containing 16-24% is commonly and widely usedin humans to stop bleeding during surgery, and to prevent the formationand reformation of postsurgical adhesions. Studies also show that suchoxidized celluloses possess antibacterial activity [Abaev et al.(1986)], promote bone regeneration [Finn et al. (1992)], and are usefulin periodontal therapy [Pollack et al. (1992)]. These properties havebeen attributed to the polyglucuronic acid structure of oxidizedcellulose.

[0004] Alpaslan et al. (1997) showed that oxidized cellulose is welltolerated by soft tissues. C. C. Canvern (1996) reported that oxidizedcellulose soaked with thrombin is helpful in preventing acute kinking ofcoronary bypass grafts and postoperative hemorrhage due to oozing fromthe anastomotic suture lines, devastating complications of myocardialre-vascularization. U.S. Pat. No. 5,169,840 discloses that oxidizedcellulose is also useful to potentiate antibody production in responseto vaccine antigens.

[0005] Oxidized cellulose has also been investigated as an immobilizingmatrix for amine drugs, enzymes, and proteins. For instance, Dol'berg etal. (1974) reported the preparation, characterization and evaluation ofionic complexes of kanamycin sulfate and sulfanilamide with oxidizedcellulose. Compared to free drugs, these complexes exhibited biologicaleffects in excess of twenty days, and were readily absorbed in vivo.Adrenalone complexed with oxidized cellulose showed prolonged antisepticand anesthetic activities and was useful for treating parodontosis.Balakleevskii (1986); Sonavaria, (1995). Firsov et al. (1987) found thatthe ionic complexes of lincomycin and oxidized cellulose were lessirritating to the skin and mucous membranes. Implants of an ioniccomplex of gentamycin and oxidized cellulose showed antibioticconcentrations at the site of implantation for 30 days.

[0006] Recently, several chemotherapeutic agents, such as photrin[Kaputskii et al. (1995)], dimetpramide [Kosterova et al. (1993)], and amixture of methotrexate and hydroxythiamine [Zimatkina (1996)], havebeen immobilized on oxidized cellulose and were shown to be moreeffective than the respective free drugs. When trypsin was immobilizedon oxidized cellulose, it exhibited higher activity than when it wasimmobilized on phosphate or amino functionalized cellulose. Alinovskayaet al. (1989). Increased activity was also observed when proteinase, anenzyme, was immobilized on oxidized cellulose. Alinovskaya (1988).

[0007] Studies show that the carboxyl content and degree ofpolymerization (DP) of oxidized cellulose play important roles in thedegradation of oxidized cellulose in vitro and in vivo. In general, thehigher the carboxyl content, or the lower the DP, the faster the rate ofdegradation of oxidized cellulose. Ashton (1968). In-vitrosolubilization and degradation studies have shown oxidized cellulose tobe readily hydrated. About 90% of oxidized cellulose (carboxyl content12-18%) converts to soluble substances within 21 days in a pH 7.4 buffersolution. An analysis of the resulting oxidized cellulose solution byhigh performance liquid chromatography (HPLC) suggests that the polymerreadily undergoes chain shortening to yield oligomers. In the presenceof plasma or serum, the oligomers are further hydrolyzed to smallfragments, such as glucose, glucoronic acid and 2 and 3-carbonfragments. It has been suggested that the degradation of oxidizedcellulose to oligomers occurs due to the presence of the carboxyl groupat the C-6 position, which increases the susceptibility of theintersaccharide linkage to hydrolytic cleavage.

[0008] Dimitrijevzh et al. (1990) studied the degradation of oxidizedcellulose (carboxyl content 12-18%) in vivo. They implanted oxidizedcellulose onto rabbit uterine horn abrasions. Degradation was found tobe rapid, and the oligomeric products produced were present primarily inthe peritoneal fluid at the implantation site. No accumulation wasobserved in either the serum or urine. It is suggested that thedegradation of oxidized cellulose involves an initial chemicaldepolymerization step, followed by an enzymatic hydrolysis reactionmediated by glycosidases endogenous to peritoneal macrophages.

[0009] Compared to other biodegradable polymers (e.g., poly(lactides),poly(glycolides), poly(lactide-co-glycolide) copolymers, poly (β-malicacid), etc.), oxidized cellulose has received little consideration as apotential biomaterial or drug carrier. This is because it is practicallyinsoluble in organic solvents and water, and hence, poses little or noformulation flexibility.

[0010] Recently, U.S. Pat. No. 5,973,139 disclosed a process forproducing carboxylated cellulose esters using oxidized cellulosematerials containing at least 30 meq/kg, and preferably between 40meq/kg and 70 meq/kg (about 0.14-0.3% w/w) of carboxylic content. Inthis process, the starting cellulose source is first esterified and thenhydrolyzed to give the product. The hydroxyl content in the productranges from 0.05 to 1.0. The carboxylated cellulose esters prepared bythis method are useful in the development of coating formulations thatcan be applied to paper, plastic, metal, wood, gypsum board, concretebrick, masonary or galvanized sheets.

[0011] Another previous method in the art for preparing carboxylatedcellulose esters uses cellulose acetate butyrate as a starting material.The carboxylic groups are then introduced by treating the polymer withozone. Sand, 1987. A similar method is disclosed in European PatentApplication No. 138,703. The disadvantage to the carboxylated celluloseesters prepared according to these references, however, is that they arenot biodegradable.

[0012] The present inventors have now prepared a series of oxidizedcellulose esters that not only show solubility in aqueous alkalinebuffer solutions, but also dissolve in organic solvents, and/or water,depending on the nature of the ester moiety in the polymer. Since theester linkage undergoes hydrolysis by enzymatic and chemical means invivo and in vitro, oxidized cellulose esters of the present inventioncan be used to produce a variety of biodegradable controlled and/orsustained release pharmaceutical, agricultural, and veterinarycompositions.

[0013] Accordingly, it is a primary object of the present invention toprovide oxidized cellulose esters that exhibit solubility in aqueousalkaline solution, water and/or common organic solvents.

[0014] It is a further object of the present invention to provideoxidized cellulose esters that are biodegradable.

[0015] It is a further object of the present invention to provide amethod to modify oxidized cellulose containing 3-25% carboxylic contentto produce the corresponding alkyl, aryl or mixed alkyl-aryl esters.

[0016] It is a further object of the present invention to provideoxidized cellulose esters suitable for use as an implantable and/orinjectable biodegradable carrier for drugs, chemicals, and biologicalmacromolecules such as proteins and peptides.

[0017] It is yet a further object of the invention to provide oxidizedcellulose esters based compositions that may serve as controlled and/orsustained-release delivery systems.

[0018] It is still a further object of the present invention to provideoxidized cellulose ester-based film forming agents suitable forproducing biodegradable medicated films for use in the treatment of skindisorders.

[0019] It is a further object of the present invention to provide anoxidized cellulose ester-based coating system useful in producingenteric-coated solid pharmaceuticals.

[0020] It is yet a further object of the present invention to provide amethod of producing oxidized cellulose esters that are economical tomanufacture.

[0021] The methods and means of accomplishing each of the above objectswill become apparent from the detailed description, preferredembodiments, and specific examples that follow hereafter.

SUMMARY OF THE INVENTION

[0022] This invention describes the preparation and composition ofoxidized cellulose esters suitable for use as film-forming agents, drugcarriers, and immobilizing matrix in the development of biodegradablecontrolled and/or sustained release pharmaceutical, agricultural, andveterinary compositions.

[0023] In accordance with the invention, oxidized cellulose esters areproduced by reacting oxidized cellulose powder containing at least 3% byweight carboxylic content with an acylating agent in an appropriatesolvent at a temperature ranging between 5-125° C. for 15 minutes to 12hours. The oxidized cellulose esters of this invention are not onlysoluble in aqueous alkaline solutions but dissolve in water and/ororganic solvents, depending on the nature of the ester moiety and degreeof substitution. In addition, they are relatively less expensive toproduce than some of the most commonly and widely used biodegradablepolymers.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention relates to the development of novelbiodegradable oxidized cellulose esters. It has now been discovered thatoxidized cellulose treated with an organic acid, organic acid/acidanhydride combination, or an organic acid chloride undergoes anesterification reaction to form novel biodegradable, oxidized, celluloseesters. These modified oxidized celluloses exhibit solubility in aqueousalkaline solutions, water and/or common organic solvents, such asacetone and alcohol, depending on the nature of the ester groups anddegree of substitution.

[0025] In comparison to previously made oxidized cellulose esters, theproducts of this invention offer a new class of biodegradable polymersthat may be used as biomaterials and as drug carriers in medicine,pharmaceutics, agriculture, and veterinary fields. In addition, theseoxidized cellulose esters are less expensive to produce than some of themost commonly and widely used biodegradable polymers, such aspoly(lactide-co-glycolide) copolymer.

[0026] The oxidized cellulose esters of this invention are capable offorming a monolithic transparent film when cast from the solution in anappropriate organic solvent or aqueous dispersion/solution in watercontaining small but adequate amounts of plasticizer. Due to thebiodegradable nature of these oxidized cellulose esters, such solutionscan be used in the preparation of biodegradable films or to producebiodegradable coatings on solid implants for controlling the release ofentrapped medicament.

[0027] Owing to the presence of free carboxyl groups, the oxidizedcellulose esters of this invention may also be used as prodrug carriers.Agents containing carboxylic acid, amine or hydroxyl group(s) can belinked to oxidized cellulose esters via an anhydride, amine or esterlinkage. Like the parent polymer, oxidized cellulose esters of thisinvention are also capable of forming ionic complexes with amine drugs,proteins, enzymes, or other biological molecules, and hence may serve asan immobilizing agent for these agents. Owing to their solubility inorganic solvent, oxidized cellulose esters can also be readilyformulated into drug encapsulated micro- or nanospheres usingconventional methods known in the art, such as spray drying,emulsification, coacervation, and reversible salting out. See. e.g.Giunchedi (1995); Watts et al. (1990); Arshady (1990); Ibrahim et al.(1992); and Allemann et al. (1992).

[0028] The oxidized esterified celluloses of this invention have thefollowing general structures I and II:

[0029] wherein:

[0030] X is H, Na, K, Ca, NH₄, or NEt₃H;

[0031] R is H; CF₃; (CH₂)_(n)CH₃, where n is from 0 to 18, andpreferably 0 to 5; (CH₂)_(n)COOH, where n is from 1 to 8, and preferably2 to 4; CY═CZCOOH, 5 where Y and Z are independently selected from thegroup consisting of hydrogen, methyl, branched alkyl having from 1 to 20carbon atoms and from one to three cis or trans double bonds; branchedalkenyl having from 1 to 20 carbon atoms and having from one to threecis or trans double bonds; CY═CH₂, where Y is H, methyl, or phenyl;CH═CHY, where Y is C₆H₅; CH═CYCOOH, where Y is H or CH₃;(CH₂)₈CH═CH(CH₂)₈CH₃; or C₆H₍₂₋₆₎(COOH)₀₋₄, CH₂CH(COOH)CH₂—COOH;

[0032] w, is 0.1-1.0;

[0033] x is 0.1-2.0; and

[0034] n is 30-1500.

[0035] and

[0036] wherein:

[0037] X is H, Na, K, Ca, NH₄, or NEt₃H;

[0038] R, R′, and R″ are each selected from the group consisting of: H;CF₃; (CH₂)_(n)CH₃, where n is from 0 to 18, preferably 0 to 2;(CH₂)_(n)COOH, where n from 1 to 8, preferably 2 to 4; CY═CZCOOH, whereY and Z are independently selected from the group consisting ofhydrogen, methyl, branched alkyl having from 1 to 20 carbon atoms andfrom one to three cis or trans double bonds; branched alkenyl havingfrom 1 to 20 carbon atoms and having from one to three cis or transdouble bonds; CY—CH₂, where Y is H, methyl, or phenyl; CH═CHY, where Yis C₆H₅; CH═CYCOOH, where Y is H or CH₃; (CH₂)₈CH═CH(CH₂)₈CH₃; orC₆H₍₂₋₆₎(COOH)₀₋₄, CH₂CH(COOH)CH₂—COOH;

[0039] w is 0.1-1.0;

[0040] x is 0.1-1.9;

[0041] y is 0.1-1.9; and

[0042] n is 30-850.

[0043] Oxidized cellulose containing at least 3% by weight of carboxylic(COOH) content, and preferably 3-25% content, is used as the startingmaterial in the manufacture of the oxidized cellulose esters of thisinvention. Various methods of preparing oxidized celluloses are wellknown in the art, and are described in the following publications, thedisclosures of which are hereby expressly incorporated by reference:Heinze et al. (1998); Netherland Patent 77, 111, 034 (1979); U.S. Pat.No. 2,756,112 (1956); Walimbe et al. (1978); C. Bertocchi et al. (1995);E. V. Gert et al. (1995); and Heinze et al. (1993).

[0044] The cellulose used in the preparation of oxidized cellulose, thestarting cellulose material for oxidized cellulose esters of thisinvention, can be from any source, including cotton linters, alphacellulose, hard and soft wood pulp, regenerated cellulose, amorphouscellulose, low crystallinity cellulose, powdered cellulose, mercerizedcellulose, bacterial cellulose and microcrystalline cellulose.Illustrative methods can be found in the following publications, thedisclosures of which are hereby incorporated by reference: Powderedcellulose: U.S. Pat. Nos. 4,269,859 and 4,438,263; Low crystallinitycellulose: U.S. Pat. Nos. 4,357,467; 5,674,507; Wei et al. (1996);Microcrystalline cellulose: U.S. Pat. Nos. 2,978,446, 3,146,168, and3,141,875, Chem Abstr. 111 (8) 59855w, 111 (8) 59787a, 108 (19) 152420y,104 (22) 188512m, 104 (24) 209374k; CA 104 (24) 193881c, 99 (24)196859y, 98 (12) 95486y, 94 (9) 64084d, and 85 (8) 48557u.

[0045] Prior to treatment in accordance with the methods and solvents ofthis invention, the oxidized cellulose is preferably treated with aswelling agent for 5-120 minutes, and preferably for about 30-60minutes, at room temperature. The swelling agent should be used in anamount sufficient to soak the oxidized cellulose. Use of the swellingagent prior to esterification increases the rate of reaction and allowsthe reaction to occur at a lower temperature (by about 5-25° C.).Further, pretreatment with a swelling agent allows the esterificationreaction to be conducted at a lower temperature. Examples of suitableswelling agents include, but are not limited to phosphoric acid,isopropyl alcohol, aqueous zinc chloride solution, water, amines, etc.Following pretreatment, the swelled oxidized cellulose is preferablywashed with water, and then with the solvent of the reaction asdescribed below.

[0046] The oxidized cellulose source may then be acylated in one of twomanners. Method (1) involves treating the cellulose with an organicacid, either alone or in the presence of an acid anhydride. Organicacids and acid anhydrides suitable for this purpose are C₁-C₅ organicacids and/or anhydrides, with about C₁-C₃ being preferred. If ananhydride is used, it may be the anhydride corresponding to the organicacid (i.e. acetic acid/acetic anhydride), or a different anhydride. If anon-corresponding anhydride is used, the resulting oxidized celluloseester product will be a mixed esters.

[0047] Examples of organic acids that can be used alone include formicacid, trifluroacetic acid, and acetic acid. Examples of organic acidsand their corresponding anhydrides include, but are not limited to,acetic acid/acetic anhydride, propionic acid/propionic anhydride, orbutyric acid/butyric anhydride, valeric acid/valeric anhydride, caproicacid/caproic anhydride, caprylic acid/caprylic anhydride, nonanoicacid/nonanoic anhydride, capric acid/capric anhydride, lauricacid/lauric anhydride, myristic acid/myristic anhydride, palmiticacid/palmitic anhydride, heptadecanoic acid/heptadecanoic anhydride,stearic acid/stearic anhydride, arachidic acid/arachidic anhydride,behenic acid/behenic anhydride, maleic acid/maleic anhydride, succinicacid/succinic anhydride, mellitic acid/mellitic anhydride, phthallicacid/phthallic anhydride, oleic acid/oleic anhydride, linoleicacid/linoleic anhydride, leinolenic acid/leinolenic anhydride, etc.

[0048] In accordance with Method (1), the oxidized cellulose ispreferably treated in the presence of an acid catalyst, for e.g.sulfuric acid, o-phosphoric acid, perchloric acid, and zinc chloridesolution. If used, the acid catalyst should be present in aconcentration ranging from about 0.1-10%, preferably 0.5-2%, by weightof the organic acid anhydride. In general, the higher the reactiontemperature the lower the concentration of the acid catalyst, and viceversa, is required.

[0049] Method (2) involves treatment of the oxidized cellulose with anexcess of an organic acid chloride or organic acid anhydride in anorganic solvent such as dimethylsulfoxide (DMSO), N,N′-dimethylacetamide(DMA), N′N′-dimethylformamide (DMF), dioxane, or the like, in thepresence of a base catalyst. Appropriate organic acid chlorides areC₁-C₂₀ compounds, with about C₁-C₁₈ being preferred. Specific examplesof organic acid chlorides include, but are not limited to, caproylchloride, heptanoyl chloride, octanoyl chloride, capryl chloride,undecanoyl chloride, lauroyl chloride, tridecanoyl chloride, myristoylchloride, pentadecanoyl chloride, palmitoyl chloride, heptadecanoylchloride, steroyl chloride, arachidoyl chloride, and behenoyl chloride.Examples of unsaturated acid chlorides include palmitileoyl chloride(cis-9), oleoyl chloride (cis-9), linoleoyl chloride (cis-9,12),linolelaidoyl chloride (trans-9,12), γ-linolenoyl chloride (cis-6,9,12),etc. Examples of unsaturated acids that can be converted to thecorresponding acid chlorides by the method known in the art includeundecylenic acid, myristoleic acid (cis-9), myristelaidic acid(trans-9), palmitelaidic acid (trans-9), sterolic acid (9-ynoic), etc.

[0050] Examples of appropriate base catalysts include, but are notlimited to pyridine, triethylamine, pyridine derivatives, etc. Theamount of the base catalyst that can be used varies from reaction toreaction, typically ranging from 2% to 20% by weight of the amount ofthe anhydride or acid chloride used in the reaction. In some reactions,it could also be used both as a solvent and as a catalyst. For bothMethod (1) and (2), the acylating reaction should occur at a temperatureranging from about 5-125° C., and preferably between about 15-75° C. Thereaction should be allowed to continue for a time period of 0.5-12hours, and preferably between about 2-6 hours. The resulting solid isthen preferably filtered, washed with water to a neutral pH range ofbetween about pH 6-8, and then dried using conventional methods such asair-drying, vacuum drying, etc. Yields of the various oxidized celluloseesters prepared by the methods of this invention range between about70-95%.

[0051] As a general rule, the hydrophobic character of the oxidizedcellulose esters of this invention increases with increasing length ofthe carbon chain in the ester moiety. For instance, in the free acidform, the oxidized cellulose esters are soluble in alcohols, ketones,aqueous alcohol, aqueous acetone, DMSO, DMA, DMF, or mixtures thereofOwing to the presence of free carboxylic groups, oxidized celluloseesters of this invention are soluble in mild to strong aqueous alkalisolutions. The pH at which the dissolution occurs depends on the natureof the ester moiety present in the polymer and degree of substitution.For example, oxidized cellulose acetate is insoluble in water and acidicaqueous solutions, but swells in pH 7 and higher buffer solutions, andeventually dissolves.

[0052] In comparison, oxidized cellulose maleate or other unsaturatedalkyl or alkenyl substituted esters containing one or more freecarboxylic groups on the ester moiety as pendant groups hydrate in waterand dissolve to give a viscous solution.

[0053] The aryl substituted esters of oxidized cellulose, irrespectiveof the absence or presence of the free carboxylic group, neither swellnor dissolve in water. They are insoluble in acidic aqueous solutions,but dissolve in mild to strong aqueous alkaline solutions. They aresoluble in alcohol, acetone, and a variety of other simple and mixedorganic solvents. The mixed oxidized cellulose esters exhibit solubilityintermediate to those of the parent alkyl and aryl cellulose esters.

[0054] Oxidized cellulose esters of this invention are capable offorming a monolithic transparent film when cast from the solution in anappropriate organic solvent system containing small but adequate amountsof a plasticizer or a mixture of two plasticizers. Preferredconcentrations of plasticizer range from about 0.1-35% by weight. Thetypes of plasticizers that can be used depend on the nature of thepolymer being used. Examples of plasticizers included but not limitedto: triethyl citrate, diethyl citrate, dibutyl phthalate diethylphthalate, triacetin, glycerin, etc. Other formulation additives such aschemical release flux regulators and antifoaming agents can also beadded to the solution. The use of a small but adequate amount ofplasticizer reduces the interaction forces between polymer chains and asa result facilitates coalescence between boundaries of particles andconsequently produces a homogeneous monolithic film.

[0055] Oxidized cellulose esters solutions containing drugs can be spraydried or processed by spray drying or other conventional emulsificationapproaches to produce micropaticles/microspheres ornanoparticles/nanospheres. The general procedures for preparing suchcompositions are well known to those skilled in the art.

[0056] Adequately plasticized solutions of oxidized cellulose esters arealso useful in coating tablets to form controlled/sustained releasedosage forms. Such coatings withstand the stomach pH, but dissolve inthe more alkaline pH of the small intestine. Other commonly used filmforming polymers can be mixed with such solutions and used.

[0057] The formulation of pharmaceutically-acceptable dosage forms iswell known in the art. As used herein, the term“pharmaceutically-acceptable” refers to the fact that the preparation iscompatible with the other ingredients of the formulation and is safe foradministration to humans and animals.

[0058] Oral dosage forms encompass tablets, capsules, and granules.Preparations which can be administered rectally include suppositories.Other dosage forms include suitable solutions for administrationparenterally or orally, and compositions which can be administeredbuccally or sublingually.

[0059] The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself well known in the art. Forexample the pharmaceutical preparations may be made by means ofconventional mixing, granulating, dragee-making, dissolving,lyophilizing processes. The processes to be used will depend ultimatelyon the physical properties of the active ingredient used.

[0060] Suitable excipients are, in particular, fillers such as sugarsfor example, lactose or sucrose mannitol or sorbitol, cellulosepreparations and/or calcium phosphates, for example, tricalciumphosphate or calcium hydrogen phosphate, as well as binders such asstarch, paste, using, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents may be added,such as the above-mentioned starches as well as carboxymethyl starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as sodium alginate. Auxiliaries are flow-regulating agentsand lubricants, for example, such as silica, talc, stearic acid or saltsthereof, such as magnesium stearate or calcium stearate and/orpolyethylene glycol.

[0061] For this purpose concentrated sugar solutions may be used, whichmay optionally contain gum arabic, talc, polyvinylpyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures.

[0062] The following examples are provided to illustrate but not limitthe invention. Thus, they are presented with the understanding thatvarious modifications may be made and still be within the spirit of theinvention.

EXAMPLE 1 Preparation of Oxidized Cellulose Acetate (OCA)

[0063] (1) 2 g of oxidized cellulose (carboxylic content 13.7%) wasreacted with 10 ml acetic anhydride and 10 ml acetic acid in thepresence of 0.5 ml sulfuric acid at 30-40° C. for 2 hours. The reactionmixture was then poured into 50 ml ethyl ether. The resulting solid wasfiltered, washed with water to pH 6 and then dried in a vacuum oven at50° C. to produce the desired product (yield 67%).

[0064] (2) 2 g. of oxidized cellulose was soaked in water for 15 min.and then washed first with acetone and then with acetic acid. The wetoxidized cellulose was then added to a mixture of acetic acid (25 ml),acetic anhydride (25 ml), and sulfuric acid (0.75 g) with constantstirring. An immediate exothermic reaction occurred and the reactionmixture turned into a clear solution. The stirring was continued at roomtemperature for one hour and then poured into ether. The white tooff-white solid that formed was filtered, washed with water, and thendried in a vacuum oven at 60° C. (yield 94%).

[0065] The FT-IR, ¹H NMR and ¹³C NMR spectral date are as follows:

[0066] FT-IR spectrum (FIG. 2): 3500-3700, 2952, 2894, 1753, 1233, and1047 cm⁻¹.

[0067]¹H NMR spectrum (FIG. 3): 1.84-2.17 ppm and 3.5-5.5 ppm ¹³C NMRspectrum (FIG. 4): 167-170, 99-100, 67-76, 61-62, and 20-21 ppm.

EXAMPLE 2 Preparation of Oxidized Cellulose Succinate (OCS)

[0068] 1.0 g of oxidized cellulose (COOH content 20%) was taken in 10 mlof dimethyl sulfoxide. To the stirred solution, 0.19 triethylamine wasadded. The reaction mixture was stirred for 10-15 min. and then 20 g. ofsuccinic anhydride was added. The reaction mixture was then heated at60° C. for 4 hours with stirring. To the reaction mixture, 0.1N HCl wasadded until the pH of the solution was between 1-3. The reaction mixturewas poured into iso-propanol (50 ml). The solid precipitated wasfiltered, washed first with iso-propanol and then with acetone to give0.85 g of the product (yield 85%).

[0069] The FT-IR, ¹H NMR and 13C NMR spectral date are as follows:

[0070] FT-IR spectrum: 3443-3700, 1736

[0071]¹H NMR spectrum: 2.4 ppm

EXAMPLE 3

[0072] Preparation of Oxidized Cellulose Laurate (OCL)

[0073] 2.0 g. of oxidized cellulose (COOH content 13%) and 20 ml ofpyridine were taken in a round bottom flask and vigorously stirred. 3.0ml of lauric chloride was then added dropwise and the reaction mixturewas heated at 70° C. for four hours. The reaction mixture was thenpoured in acetone. The resulting solid was filtered and resuspended inwarm acetic acid. The residue was filtered and washed first with waterand then with acetone and finally dried in a vacuum oven at 50° C.

[0074] The FT-IR, ¹H NMR and ¹³C NMR spectral date are as follows:

[0075] FT-IR spectrum: 2927, 2857, and 1754 cm⁻¹.

EXAMPLE 4 Preparation of Oxidized Cellulose Maleate (OCM)

[0076] 3.0 g of oxidized cellulose (COOH content 20%) was taken in 15 mlof dimethyl sulfoxide. 0.57 g of triethylamine and 4.88 g of malicanhydride were then added in the order written. The reaction mixture washeated at 60° C. for six hours. It was poured in iso-propanol. Theresulting solid was filtered, dissolved in a small amount of water, andthen dialyzed against water to remove any water-soluble (inorganic)salts. The dialyzed sample was concentrated on a rotoevaporator toproduce the desired product (2.0 g). The FT-IR, ¹H NMR and ¹³C NMRspectral date are as follows:

[0077] FT-IR: 3500-3700 cm⁻¹, 3067, 3016, 1738, 1223, and 1061 cm⁻¹.

[0078]¹H NMR (in D₂O): δ 6.90, 6.30, 6.23, and 3.5-6.0 ppm.

[0079]¹³C NMR (in D₂O): δ 173, 166, 140, 136, 122, 103, 94, 7 and 2-81ppm

EXAMPLE 5 Preparation of Oxidized Cellulose Phthalate (OCP)

[0080] This compound was prepared according to the procedure describedin Example 2. The quantities of various agents used were: oxidizedcellulose (COOH content 20%; 2.0g), triethylamine (0.38 g), andphthallic anhydride (2.5 g). The yield of oxidized cellulose phthalatewas 1.8 g (90%). The FT-IR, ¹H NMR and ¹³C NMR spectral date are asfollows:

[0081] FT-IR: 3400-3700, 3073, 1736, 1260, and 1062 cm⁻¹

[0082]¹H NMR (in DMSO-d₆): δ 7.56-7.73 and 4.0-6.0.

[0083]¹³C NMR (in DMSO-d₆): δ 173, 166, 140, 136, 122, 103, 94, and72-81

EXAMPLE 6 Preparation of Oxidized Cellulose Acetate Phthalate (OCAP)

[0084] 1.0 g of oxidized cellulose (COOH 20%) was soaked in 10 ml waterfor 10 min. and then filtered and washed with 10 ml dimethylformamide(DMF). The treated oxidized cellulose was then reacted with 2.8 g ofphthallic anhydride in 10 ml DMF and 2 ml pyridine at 60° C. for 2 hourswith constant stirring. The reaction mixture was then cooled to 55° C.To the reaction mixture then 5 ml of acetic anhydride was added and theheating was continued for two hours. The reaction mixture was thenacidified with aqueous 0.1N HCl. This was followed by addition of 100 mlof iso-propanol. The resulting solid was filtered, washed with water topH 6, and dried at 50° C. in a vacuum oven. The yield of OCAP was 1.8 g(90%).

[0085] The FT-IR, ¹H NMR and ¹³C NMR spectral date are as follows:

[0086] FT-IR: 3400-3700, 3062, 2965, 2907, 1267, and 1278 cm⁻¹

[0087]¹H NMR (in DMSO-d₆): δ 7.6, 4.0-6.0, and 2.012-1.882.

[0088]¹³C NMR (in DMSO-d₆): δ 169.3 (168.2-170.4), 131.7 (131-132.3),128.8 (129), 99, 71.9 (70.9-73.2), 61.5 (60-63), 20.4 (20.33-20.45) ppm.

[0089] Having described the invention with reference to particularcompositions, theories of effectiveness, and the like, it will beapparent to those of skill in the art that it is not intended that theinvention be limited by such illustrative embodiments or mechanisms, andthat modifications can be made without departing from the scope orspirit of the invention, as defined by the appended claims. It isintended that all such obvious modifications and variations be includedwithin the scope of the present invention as defined in the appendedclaims. The claims are meant to cover the claimed components and stepsin any sequence which is effective to meet the objectives thereintended, unless the context specifically indicates to the contrary.

[0090] All articles cited herein and in the following list are herebyexpressly incorporated in their entirety by reference.

CITATIONS

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What is claimed is:
 1. A biodegradable, oxidized cellulose ester.
 2. Abiodegradable, oxidized cellulose ester according to claim 1 containingat least 3% by weight carboxyl content.
 3. A biodegradable, oxidizedcellulose ester according to claim 2 containing between about 3-25% byweight carboxyl content.
 4. An oxidized cellulose ester according toclaim 1 having the following general formula I or II:

wherein: X is selected from the group consisting of H, Na, K, Ca, NH₄,and NEt₃H; R is selected from the group consisting of H; CF₃;(CH₂)_(n)CH₃, where n is from 0 to 18; (CH₂)_(n)COOH, where n is from 1to 8; CY═CZCOOH, where Y and Z are each one of hydrogen, methyl,branched alkyl having from 1 to 20 carbon atoms and from one to threecis or trans double bonds; branched alkenyl having from 1 to 20 carbonatoms and having from one to three cis or trans double bonds; CY═CH₂,where Y is H, methyl, or phenyl; CH═CHY, where Y is C₆H₅; CH═CYCOOH,where Y is H or CH₃; (CH₂)₈CH═CH(CH₂)₈CH₃; or C₆H₍₂₋₆₎(COOH)₀₋₄,CH₂CH(COOH)CH₂—COOH; w is 0.1-1.0; x is 0.1-2.0; and n is 30-1500. and

wherein: X is selected from the group consisting of H, Na, K, Ca, NH₄,and NEt₃H; R, R′, and R″ are each selected from the group consisting of:H; CF₃; (CH₂)_(n)CH₃, where n is from 0 to 18; (CH₂)_(n)COOH, where nfrom 1 to 8; CY═CZCOOH, where Y and Z are independently selected fromthe group consisting of hydrogen, methyl, branched alkyl having from 1to 20 carbon atoms and from one to three cis or trans double bonds;branched alkenyl having from 1 to 20 carbon atoms and having from one tothree cis or trans double bonds; CY—CH₂, where Y is H, methyl, orphenyl; CH═CHY, where Y is C₆H₅; CH═CYCOOH, where Y is H or CH₃;(CH₂)₈CH═CH(CH₂)₈CH₃; or C₆H₍₂₋₆₎(COOH)₀₋₄, CH₂CH(COOH)CH₂—COOH; w is0.1-1.0; x is 0.1-1.9; y is 0.1-1.9; and n is 30-850.
 5. An oxidizedcellulose ester according to claim 4 that has the general structure I orII, whereby R is (CH₂)_(n)CH₃, and n is 0 to
 5. 6. An oxidized celluloseester according to claim 4 that has the general structure I or II,whereby R is (CH₂)_(n)COOH, and n is 2 to
 4. 7. An oxidized celluloseester according to claim 1 that is dried.
 8. An oxidized cellulose esteraccording to claim 1 that is in a monolithic transparent film.
 9. Anoxidized cellulose ester according to claim 1 that is in a biodegradablecoating.
 10. An oxidized cellulose ester according to claim 1 that ispresent in a product selected from the group consisting of apharmaceutical, an agricultural product, and a veterinary composition.11. An oxidized cellulose ester according to claim 1 that is soluble inat least one solvent selected from the group consisting of water,ketones, esters, glycol ethers, glycol ether acetates, alcohols,methylene chloride, halogenated solvents, and aprotic solvents.
 12. Anoxidized cellulose ester according to claim 11 whereby the aproticsolvents are selected from the group consisting of DMSO, DMA, DMF, andn-methyl-2-pyrrolidone.
 13. A method of making an oxidized celluloseester comprising: oxidized cellulose containing at least 3% by weightcarboxylic content to form an oxidized cellulose ester.
 14. A methodaccording to claim 13 whereby the acylating step comprises: reacting theoxidized cellulose with an organic acid.
 15. A method according to claim14 whereby the organic acid is a C₁-C₃ organic acid.
 16. A methodaccording to claim 13 whereby the acylating step comprisese reacting thecellulose with an organic acid and an acid anhydride.
 17. A methodaccording to claim 16 whereby the acid anhydride and the organic acideach have the same number of carbons.
 18. A method according to claim 13further including the step of soaking the oxidized cellulose with aswelling agent prior to the acylating step.
 19. A method according toclaim 18 whereby the swelling agent is selected from the groupconsisting of phosphoric acid, isopropyl alcohol, aqueous zinc chloridesolution, water, and an amine.
 20. A method according to claim 18whereby the oxidized cellulose is soaked in the swelling agent for atime period of between about 5 to 120 minutes.
 21. A method according toclaim 20 whereby the oxidized cellulose is soaked in the swelling agentfor a time period of between about 30-60 minutes.
 22. A method accordingto claim 13 whereby the oxidized cellulose is acylated in the presenceof an acid catalyst.
 23. A method according to claim 22 whereby the acidcatalyst is selected from the group consisting of sulfuric acid,o-phosphoric acid, perchloric acid, and zinc chloride solution.
 24. Amethod according to claim 13 whereby the oxidized cellulose is acylatedin the presence of an organic solvent.
 25. A method according to claim24 whereby the organic solvent is selected from the group consisting ofDMSO, DMF, DMA, and dioxane.
 26. A method according to claim 13 wherebythe acylating step comprises: reacting the oxidized cellulose with anorganic acid chloride, in an organic solvent, and a base catalyst.
 27. Amethod according to claim 26 whereby the organic acid chloride is aC₁-C₂₀ organic acid chloride.
 28. A method according to claim 26 wherebythe organic solvent is selected from the group consisting of DMSO, DMF,DMA, and dioxane.
 29. A method according to claim 26 whereby the basecatalyst is selected from the group consisting of pyridines,alkylpyridines, trialkylamines and sodium carbonate.
 30. A methodaccording to claim 13 whereby the acylating step takes place at atemperature ranging between about 5-125° C.
 31. A method according toclaim 13 whereby the acylating step takes place for a time period ofabout 0.5-12 hours.
 32. A method according to claim 13 further includingthe step of filtering the oxidized cellulose ester.
 33. A methodaccording to claim 32 further including the step of washing the oxidizedcellulose ester to a pH between about 6-8 following the filtering step.34. A method according to claim 33 further including the step of dryingthe oxidized cellulose ester following the washing step.
 35. Apharmaceutical containing the oxidized cellulose ester of claim 1.